The macromolecular structure of the nerve membrane involved in the process of excitation has been studied using both crab nerves and squid giant axons. In a project designed to gather information on which functional groups were involved in excitation, protein modifying reagents were applied to the exterior of crab nerves and to the interior of squid giant axons. It was found that modification of either histidine or sulfhydryl groups, located inside the axon, produced conduction block, but that modification of either of these groups or of amino groups on the external surface of the axon, had no effect on excitability. These observations led to the speculation that histidine and sulfhydryl groups, located intracellularly, must be involved in excitation, but that amino groups are not. In another project, proteins from squid giant axons were labeled covalently with a variety of radioactive compounds. By collecting the perfusate from internally perfused squid giant axons, labeling these proteins with 125I-Bolton-Hunter reagent, and analyzing them using polyacrylamide gel electrophoresis, it was found that a 56,000 dalton protein was released when excitability was lost due to perfusion with a chaotropic salt. When either 125I-Bolton-Hunter reagent or 3H-DNFB were introduced into a squid axon, the labeling efficiency of these compounds was increased by electrically stimulating the axon. When a squid giant axon was incubated in a solution containing AT32P(gamma), three major protein bands were found to be phosphorylated (molecular weights: 400,000, 200,000 and 12,000). The phosphorylation of two of these proteins was sensitive to electrical stimulation. BIBLIOGRAPHIC REFERENCES: Inoue, I., Pant, H.G., Tasaki, I. and Gainer, H.: Release of proteins from the inner surface of squid axon membrane labeled with tritiated N-ethylmaleimide. J. Gen. Physiol. 68: 385-395, 1976. Tasaki, T.: Chronaxie and transitional decrement: A review of Dr. Davis' contributions to physiology of nerve fibers. In Hirsh, S.K., Eldredge, D.H., Hirsh, I.J. and Silverman, S.R. (Eds.): Hearing and Davis: Essays Honoring Hallowell Davis. St. Louis, Washington Univ. Press, 1976, pp. 1-10.